[go: up one dir, main page]

CN101208311A - Pyrazine-2-carboxamide derivatives as mGluR5 antagonists - Google Patents

Pyrazine-2-carboxamide derivatives as mGluR5 antagonists Download PDF

Info

Publication number
CN101208311A
CN101208311A CNA200680007159XA CN200680007159A CN101208311A CN 101208311 A CN101208311 A CN 101208311A CN A200680007159X A CNA200680007159X A CN A200680007159XA CN 200680007159 A CN200680007159 A CN 200680007159A CN 101208311 A CN101208311 A CN 101208311A
Authority
CN
China
Prior art keywords
alkyl
compound
chf
formula
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA200680007159XA
Other languages
Chinese (zh)
Other versions
CN101208311B (en
Inventor
G·杰什科
S·科茨威斯基
R·H·P·波特
E·维埃拉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of CN101208311A publication Critical patent/CN101208311A/en
Application granted granted Critical
Publication of CN101208311B publication Critical patent/CN101208311B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Addiction (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)

Abstract

The present invention is concerned with novel pyrazine 2-carboxyamide derivatives of the general formula (I) useful as metabotropic glutamate receptor antagonists: formula (I) wherein R<1>, R<2> and R<3> are as defined in the description and claims.

Description

Pyrazine-2-carboxamides derivatives as the mGluR5 antagonist
The present invention relates to can be used as the novel pyrazine-2-carboxamides derivatives of the general formula (I) of metabotropic glutamate receptor (metabotropic glutamatereceptor) antagonist:
Figure S200680007159XD00011
Wherein
R 1For having formula (II) or 5-(III) or 6-unit ring separately:
Figure S200680007159XD00012
R 2Be H, C 1-C 7-alkyl, C 3-C 6-cycloalkyl or-(CH 2) m-R a
R 3Be H, the aryl or the heteroaryl that are randomly replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R d
Perhaps randomly by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R 5Be C 1-C 7-alkyl, C 1-C 7-alkyl-C 3-C 6-cycloalkyl ,-(CH 2) n-O-R f, C 3-C 8-alkenyl-O-R f,-(CH 2) n-NR gR h,-C 2-C 6-alkenyl-NR gR hOr-(CH 2) n-R e
R aFor-O-C 1-C 7-alkyl or-OH;
R bBe C 1-C 7-alkyl, NH 2Or-O-C 1-C 7-alkyl;
R cFor-OH, NH 2Or NH-(CO)-O-C 1-C 7-alkyl;
R dBe C 1-C 7-alkyl ,-NH 2,-NH-C 1-C 7-alkyl or-N-two (C 1-C 7-alkyl);
R eFor-OH ,-CH 2F ,-CHF 2,-CF 3Or-O-(CO)-C 1-C 7-alkyl;
R fBe C 1-C 7-alkyl, C 3-C 8-alkenyl, C 3-C 6-cycloalkyl, phenyl, benzyl or-(CO)-R ';
R g, R hBe H, C independently 1-C 7-alkyl, C 3-C 6-cycloalkyl, C 3-C 8-alkenyl, phenyl, benzyl or-(CO)-R ', perhaps R gAnd R hAlso can form 5-to the 7-unit's heterocycle or the heteroaryl ring that are randomly replaced with the nitrogen-atoms that they connected by 1 or 2 OH;
R ' is NH 2,-NH-C 1-C 7-alkyl, C 1-C 7-alkyl or C 1-C 7-alkoxyl group;
M is 1 to 4;
N is 2 to 6;
With and pharmacologically acceptable salt.
Bonnefous etc. are at Dipyridyl amides:potent metabotropic glutamatesubtype 5 (mGlu5) receptor antagonists; Bioorganic﹠amp; Medicinal chemistryLetters has described the compound that can be used as I group metabotropic glutamate receptor antagonists in 2005, but unexposed compound of the present invention.In addition, Bonnefous etc. is open: for R wherein 1Be formula (I) compound of pyridin-3-yl or pyridin-4-yl, generally speaking described compound does not have activity.Now be surprisingly found out that: opposite with this discovery, the 5-position of described pyridine-2-based compound is easy to be replaced by fluorine atom really, and the wherein R of gained 1For the formula I compound of pyridin-4-yl has activity as the mGluR5 receptor antagonist.
In addition, it has surprisingly been found that: other pyrazine-2-carboxamides derivatives but not pyridine-2-radical derivative also has the activity as the mGluR5 receptor antagonist.
In central nervous system (CNS), the transmission that the neurotransmitter that discharges by neurone and the interaction of neuroreceptor stimulate.
The compound that now has been surprisingly found out that general formula I is a metabotropic glutamate receptor antagonists.The notable feature of formula I compound is to have valuable treatment characteristic.They can be used for treatment or the receptor-mediated obstacle of prevention mGluR5.
L-glutamic acid is excitatory neurotransmitter main in the brain, plays unique effect in various central nervous systems (CNS) function.L-glutamic acid-dependent stimulation acceptor is divided into two main types.First the main type that is called short ionotropic receptor (ionotropic receptor) forms the ionic channel of part-control.Metabotropic glutamate receptor (mGluR) belongs to second main type, and also belongs to G-protein linked receptor family.
At present, 8 different members of known these mGluR families, some in them even have hypotype.According to its sequence homology, signal transduction mechanism and agonist selectivity, these 8 acceptors can be divided into three subgroups again:
MGluR1 and mGluR5 belong to the I group, and mGluR2 and mGluR3 belong to the II group, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to the III group.
The part that belongs to the metabotropic glutamate receptor of first group can be used for treatment or prophylaxis of acute and/or chronic neurological disorder such as psychosis, epilepsy, schizophrenia, alzheimer's disease, cognitive disorder and hypomnesis (memory deficit) and chronic and acute pain.
Anoxic, asystole and hypoglycemia that brain function limited (restricted brain function), cerebral blood supply insufficiency (poor bloodsupply to the brain), Spinal injury, head injury, the gestation that medicable in this respect other indication has shunt operation (bypass operation) or transplanting to cause causes.The illness that dementia, ocular injury, retinopathy, the spy that other medicable indication has gastroesophageal reflux disease (GERD), fragile X mental retardation, local asphyxia, Huntington Chorea, amyotrophic lateral sclerosis (ALS), AIDS to cause sends out property parkinson's syndrome or drug induced parkinson's syndrome and cause L-glutamic acid shortage function (glutamate-deficiency function) is as for example muscle spasm, convulsions, migraine, the urinary incontinence, obesity, nicotine habituation, opiate addiction, anxiety, vomiting, dyskinesia and depression.
By the mGluR5 disorder mediated neural acute, traumatic and chronic denaturation process is for example arranged wholly or in part, as alzheimer's disease, senile dementia, Parkinson's disease, Huntington Chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric disorders such as schizophrenia and anxiety, depression, pain and pharmacological dependence (Expert Opin.Ther.Patents (2002), 12, (12)).
Selectivity mGluR5 antagonist especially can be used for treating anxiety and pain.
The present invention relates to the pharmacologically acceptable salt of formula I compound and they, as the above-claimed cpd and the preparation thereof of pharmaceutically active substance.
The invention still further relates to according to as the above method that the described general process of formula I compound is prepared the compound of general formula I.
In addition, the invention still further relates to the medicine that contains one or more compounds of the present invention and pharmaceutically acceptable vehicle, it is used for the treatment of and prevents the receptor-mediated obstacle of mGluR5, as acute and/or chronic neurological disorder, particularly anxiety and chronic or acute pain.
The invention still further relates to compound of the present invention and pharmacologically acceptable salt thereof in the purposes of preparation in the medicine, described medicine is used for the treatment of and prevents the receptor-mediated obstacle of above-mentioned mGluR5.
No matter described term is to occur separately or make up appearance, all is suitable for the following definition of general term used in this specification sheets.
" aryl " mean by single-, two-or the monovalence ring-type aromatic hydrocarbon part formed of three-ring aromatic ring.Preferred aryl groups is C 6-C 10Aryl.Aryl can randomly be substituted as herein defined like that.The example of aryl moiety includes but not limited to the optional phenyl that replaces; naphthyl; phenanthryl; fluorenyl; indenyl; the pentalene base; the Azulene base; oxydiphenyl base (oxydiphenyl); xenyl; methylenediphenyl; the ADP base; phenylbenzene sulfinyl (diphenylsulfidyl); the phenylbenzene alkylsulfonyl; the phenylbenzene isopropylidene; benzo two _ alkyl; benzofuryl; benzodioxylyl; benzopyranyl; benzo _ piperazine base; benzo _ piperazine ketone group; the benzo piperidyl; the benzo piperazinyl; the benzopyrrole alkyl; the benzo morpholinyl; methylenedioxyphenyl; ethylenedioxy phenyl etc. comprise its partially hydrogenated derivative.
" C 1-C 7Alkyl " expression contains the straight chain of 1 to 7 carbon atom-or side chain-carbochain group, for example methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, n-hexyl and hereinafter those of particular instantiation among the embodiment.
" halogen " expression chlorine, iodine, fluorine and bromine.
" heteroaryl " means 5 to 12, the monocyclic, bicyclic or tricyclic group of preferred 5 to 9 annular atomses, and it has at least one aromatic ring and contains 1,2 or 3 ring hetero atom that is selected from N, O or S, and remaining annular atoms is C.Heteroaryl can be randomly replaced by 1,2,3 or 4 substituting group, wherein each substituting group be independently hydroxyl, cyano group, alkyl, alkoxyl group, alkylthio (thioalkyl), halogen, haloalkyl, hydroxyalkyl, alkoxy carbonyl, amino, ethanoyl ,-NHCOOC (CH 3) 3Or the benzyl of halogen replacement, perhaps, also can be replaced by the oxo base for the non-aromatics part of ring, other has except the person of specifying.The example of heteroaryl moieties includes but not limited to the optional imidazolyl that replaces, optional replacement _ the azoles base, the optional thiazolyl that replaces, the optional pyrazinyl that replaces, the optional pyrryl that replaces, the optional pyrazinyl that replaces, the optional pyridyl that replaces, the optional pyrimidyl that replaces, the optional indone base that replaces, the optional isoquinolyl that replaces, optional carbazole-9-the base that replaces, the optional furyl that replaces, the optional benzofuryl that replaces, the optional benzo [1 that replaces, 2,3] thiadiazolyl group, optional benzo [b] thienyl that replaces, the optional 9H-thioxanthene base that replaces, those that optional thieno-[2, the 3-c] pyridyl that replaces etc. or this paper specifically exemplify.
" C 3-C 6Cycloalkyl " expression has the carbocyclic ring of 3 to 6 carbon atoms as ring members, includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and those of particular instantiation among the embodiment hereinafter.
" 5-to 7-unit heterocycle " expression comprises the saturated rings of 1 to 6 carbon atom as ring members, and other remaining ring members atom is selected from one or more O, N and S.Preferred 5 to 7 yuan of Heterocyclylalkyls are 5 or 6 yuan of Heterocyclylalkyls.The example of 5 to 7 yuan and 5 or 6 yuan of Heterocyclylalkyls includes but not limited to the optional piperidyl that replaces, piperazinyl, high piperazinyl (homopiperazinyl), azepine _ base, pyrrolidyl, pyrazolidyl, imidazolinyl, imidazolidyl, pyridyl, pyridazinyl, pyrimidyl, _ oxazolidinyl, different _ oxazolidinyl, morpholinyl, thiazolidyl, the isothiazole alkyl, quinuclidinyl, quinolyl, isoquinolyl, benzimidazolyl-, thiadiazoles alkyl (thiadiazolylidinyl), the benzothiazole alkyl, benzopyrrole alkyl (benzoazolylidinyl), the dihydrofuran base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl, thio-morpholinyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, the dihydroquinoline base, the dihydro-isoquinoline base, tetrahydric quinoline group, tetrahydro isoquinolyl, 1-oxo-thiomorpholine, 1,1-dioxo-thiomorpholine, 1, the 4-Diazesuberane, 1,4-oxaza heptane and those of particular instantiation among the embodiment hereinafter.
The compound of formula (I) also comprises the compound of these formulas (I):
Wherein
R 1For having formula (II) or 5-(III) or 6-unit ring separately:
Figure S200680007159XD00062
R 2Be H, C 1-C 7-alkyl, C 3-C 6-cycloalkyl or-(CH 2) m-R a
R 3Be aryl or the heteroaryl that is randomly replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dPerhaps randomly by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R 5Be C 1-C 7-alkyl, C 1-C 7-alkyl-C 3-C 6-cycloalkyl ,-(CH 2) n-O-R f, C 3-C 8-alkenyl-O-R f,-(CH 2) n-NR gR h,-C 2-C 6-alkenyl-NR gR hOr-(CH 2) n-R e
R aFor-O-C 1-C 7-alkyl or-OH;
R bBe C 1-C 7-alkyl, NH 2Or-O-C 1-C 7-alkyl;
R cFor-OH, NH 2Or NH-(CO)-O-C 1-C 7-alkyl;
R dBe C 1-C 7-alkyl ,-NH 2,-NH-C 1-C 7-alkyl or-N-two (C 1-C 7-alkyl);
R eFor-OH ,-CH 2F ,-CHF 2,-CF 3Or-O-(CO)-C 1-C 7-alkyl;
R fBe C 1-C 7-alkyl, C 3-C 8-alkenyl, C 3-C 6-cycloalkyl, phenyl, benzyl or-(CO)-R ';
R g, R hBe H, C independently 1-C 7-alkyl, C 3-C 6-cycloalkyl, C 3-C 8-alkenyl, phenyl, benzyl or-(CO)-R ', perhaps R gAnd R hAlso can form 5-to the 7-unit's heterocycle or the heteroaryl ring that are randomly replaced with the nitrogen-atoms that they connected by 1 or 2 OH;
R is NH 2,-NH-C 1-C 7-alkyl, C 1-C 7-alkyl or C 1-C 7-alkoxyl group;
M is 1 to 4;
N is 2 to 6;
With and pharmacologically acceptable salt.
The compound of formula (I) also comprises these compounds of formula (Ia):
Figure S200680007159XD00071
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ia) is these compounds, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dPerhaps randomly by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined,
And pharmacologically acceptable salt, for example 6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazoles-2-yl)-amide hydrochloride.
Other compound that formula (I) compound comprises is these compounds of formula (Ib):
Figure S200680007159XD00081
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ib) is these compounds, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dPerhaps randomly by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined,
And pharmacologically acceptable salt, for example 6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (2-methyl-thiazole-4-yl)-amide hydrochloride.
Other compound that formula (I) compound comprises is these compounds of formula (Ic):
Figure S200680007159XD00082
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ic) is these compounds, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dPerhaps randomly by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined,
And pharmacologically acceptable salt, for example following compounds:
3-(3-fluoro-phenyl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides;
3-(pyridin-3-yl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides dihydrochloride;
3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides;
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-amide hydrochloride; With
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides.
Other compound that formula (I) compound comprises is the compound of these formulas (Id):
Figure S200680007159XD00091
R wherein 2, R 3And R 5As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Id) is these compounds, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,
-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOptional by C 1-C 7The heteroaryl that-alkyl replaces;
R 5Be H, C 1-C 7-alkyl or C 1-C 7-alkyl-C 3-C 6-cycloalkyl;-(CH 2) n-O-R f, C 3-C 8-alkenyl-O-R f,-(CH 2) n-NR gR h-C 2-C 6-alkenyl-NR gR hOr-(CH 2) n-R e
R b, R c, R d, R e, R f, R gAnd R hWith n as hereinbefore defined,
And pharmacologically acceptable salt, for example following compounds:
3-(5-fluoro-pyridin-3-yl amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazoles-2-yl)-acid amides;
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazoles-2-yl)-amide hydrochloride; With
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazoles-2-yl)-amide hydrochloride.
Other compound that formula (I) compound comprises is these compounds of formula (Ie):
Figure S200680007159XD00101
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ie) is these compounds and pharmacologically acceptable salt thereof,
Wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined.
Other compound that formula (I) compound comprises is these compounds of formula (If):
Figure S200680007159XD00111
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (If) is these compounds and pharmacologically acceptable salt thereof,
Wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined.
Other compound that formula (I) compound comprises is these compounds of formula (Ig):
Figure S200680007159XD00112
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ig) is these compounds and pharmacologically acceptable salt thereof,
Wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined.
Other compound that formula (I) compound comprises is these compounds of formula (Ih):
Figure S200680007159XD00121
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ih) is these compounds and pharmacologically acceptable salt thereof, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined.
Other compound that formula (I) compound comprises is these compounds of formula (Ii):
R wherein 2, R 3And R 4As hereinbefore defined.In this embodiment, R 4Can also be H.
In certain embodiments, the compound of formula of the present invention (Ii) is these compounds, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined,
And pharmacologically acceptable salt, for example following compounds:
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (5-fluoro-pyridine-2-yl)-amide hydrochloride; With
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (5-fluoro-pyridine-2-yl)-acid amides.
Other compound that formula (I) compound comprises is these compounds of formula (Ij):
Figure S200680007159XD00131
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ij) is these compounds, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined,
And pharmacologically acceptable salt, for example following compounds:
3-(pyridin-3-yl amino)-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides;
3-phenyl amino-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides; With
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (3-chloro-phenyl)-amide hydrochloride.
Other compound that formula (I) compound comprises is these compounds of formula (Ik):
Figure S200680007159XD00141
R wherein 2, R 3And R 4As hereinbefore defined.
In certain embodiments, the compound of formula of the present invention (Ik) is these compounds, wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as hereinbefore defined,
And pharmacologically acceptable salt, for example following compounds:
3-phenyl amino-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides; With
3-(5-chloro-pyridin-3-yl amino)-6-methyl-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides.
The present invention also comprises the method for preparing The compounds of this invention.
Can be according to following method preparation formula of the present invention (I) compound, this method comprises the following step: make formula (IVa) or amino protected or free amine group compound (IV):
Figure S200680007159XD00151
Compound reaction with formula (VIII):
R 1-NH 2 (VIII)
Then if desired, make gained compound deprotection and obtain the formula V compound:
Figure S200680007159XD00152
Make the reaction of formula V compound and formula (IX) compound afterwards:
R 3-X (IX)
With acquisition formula (I) compound, wherein R 1, R 2And R 3Be that halogen and R are alkyl or aralkyl (preferable methyl or ethyl) with X as hereinbefore defined.
Protecting group can be for example carbamate protecting group, such as tertbutyloxycarbonyl (BOC) or two-the protection derivative, such as-(BOC) 2Group.
Can be according to following method preparation formula of the present invention (I) compound, this method comprises the following step: the compound that makes formula (IV):
Figure S200680007159XD00153
In diazotization reaction with Sodium Nitrite (or alkyl nitrite) in the presence of the mineral acid H-X aqueous solution, finally reaction and obtain formula (VI) compound in the presence of copper (I) salt CuX:
Figure S200680007159XD00161
Make the reaction of formula (VI) compound and formula (VIII) compound afterwards:
R 1-NH 2 (VIII)
With acquisition formula (VII) compound:
Figure S200680007159XD00162
Make the reaction of formula (VII) compound and formula (X) compound afterwards:
R 3-NH 2 (X)
With acquisition formula (I) compound, wherein R 1, R 2And R 3As hereinbefore defined with X be halogen and
R is alkyl or aralkyl (preferable methyl or ethyl).
Among schema I hereinafter and the general operation step I this method is described in further detail.
Schema 1:
Figure S200680007159XD00171
General operation step I:
Step 1
The raw material of formula (IV) is for R 2=hydrogen is commercially available to be got.Can synthesize R by suitable keto-aldehyde-oxime (II) and amino-cyano group-acetic ester (III) [J.Med.Chem 1997,40,2196-2210] condensation in acetate are spent the night 2The analogue of=alkyl.Can use the compound of ordinary method separation and purifying formula (IV).
Step 2
In the solution of formula (VIII) compound in solvent (for example dry diox), add the solution of trimethyl aluminium in hexane.Add formula (IV), (IVa) or (VI) compound then.Can use ordinary method to separate and purifying formula (Va), (V) or (VII) compound.
The BOC-protection
Can obtain formula (IVa) compound by stirring-type (IV) compound and di-tert-butyl dicarbonic acid ester and 4-(N, N-dimethylamino) pyridine in the methylene dichloride that refluxes.Can use ordinary method to separate and purifying formula (IVa) compound.
The BOC-deprotection
Can obtain the formula V compound by the acidic solution that is stirred in suitable solvent (for example water and/or ethanol) Chinese style (VII) compound.Can use ordinary method to separate and purifying formula V compound.
Step 3
Can be by using for example cesium carbonate, 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xanthphos) and three (dibenzylidene-acetone) two palladium chloroform mixture (Pd 2(dba) 3.CHCl 3) make formula V compound and formula (IX) compound for catalysis coupling or acquisition formula (I) compound by making formula (VII) compound and formula (X) compound coupling.Can use ordinary method to separate and purifying formula (I) compound then.X is chlorine or fluorine atom and R therein 3In some situation for formula (IX) compound of heterocycle residue, can also under the situation that does not have palladium catalyst, use the cesium carbonate in DMF to carry out described coupling step.Can use ordinary method to separate and purifying formula (I) compound then.
The general operation Step II:
Figure S200680007159XD00181
Step 1
As selection, can be by using for example cesium carbonate, 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xanthphos) and three (dibenzylidene-acetone) two palladium chloroform mixture (Pd 2(dba) 3.CHCl 3) make formula (IV) compound and formula (IX) compound carry out the catalytic coupling of Pd and acquisition formula (X) compound.Can use ordinary method to separate and purifying formula (X) compound then.
Step 2:BOC-protection
Can be by stirring-type (X) compound and di-tert-butyl dicarbonic acid ester and 4-(N, N-dimethylamino) pyridine in the methylene dichloride that refluxes acquisition formula (XI) compound.Can use ordinary method to separate and purifying formula (XI) compound.
Step 3: saponification
Can spend the night and acquisition formula (XII) compound as cosolvent stirring-type (XI) compound and lithium hydroxide aqueous solution by at room temperature using methyl alcohol/THF mixture.Can use ordinary method to separate and purifying formula (XII) compound.
Step 4:
To formula (XII) compound, N, add coupling reagent (for example O-(benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate (TBTU)) in the solution of N-Diisopropylamine and formula (VIII) amine in solvent (for example dry DMF).After at room temperature stirring is spent the night, can use ordinary method to separate and purifying formula (XIII) compound.
Step 5: The BOC-deprotection
Can be by the acidic solution that is stirred in suitable solvent (for example water and/or ethanol) Chinese style (VIII) compound acquisition formula (I) compound.Can use ordinary method to separate and purifying formula (I) compound.
The present invention also comprises the medicament that contains one or more The compounds of this invention and pharmaceutically acceptable vehicle, and it is used for the treatment of and prevents the receptor-mediated obstacle of mGluR5 such as acute and/or chronic neurological disorder and anxiety, chronic and acute pain, the urinary incontinence and obesity.
The present invention also comprises compound of the present invention in the purposes of preparation in the medicine, and described medicine is used for the treatment of or prevents above-mentioned disease.
According to known method itself and the character of the considering salifiable compound to be transformed pharmacologically acceptable salt of preparation I compound easily.Inorganic or organic acid is suitable for forming the pharmacologically acceptable salt of alkaline formula I compound as for example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, toxilic acid, acetate, succsinic acid, tartrate, methylsulfonic acid, tosic acid etc.For example compound, basic amine or the basic aminoacids of sodium, potassium, calcium, magnesium etc. are suitable for forming the pharmacologically acceptable salt of acidic cpd to contain basic metal or alkaline-earth metal.
That has mentioned as mentioned is such, formula (I) compound and their pharmacologically acceptable salt are metabotropic glutamate receptor antagonists as mentioned above, can be used for treatment or the receptor-mediated obstacle of prevention mGluR5, as acute and/or chronic neurological disorder, cognitive disorder and hypomnesis and acute and chronic pain.Medicable neurological disorder for example has epilepsy, schizophrenia, anxiety, neural acute, traumatic or chronic denaturation process, as alzheimer's disease, senile dementia, Huntington Chorea, ALS, multiple sclerosis, the dementia that AIDS causes, ocular injury, retinopathy, the special property sent out parkinson's syndrome or drug induced parkinson's syndrome and the illness that causes L-glutamic acid shortage function are as for example muscle spasm, faint from fear, migraine, the urinary incontinence, alcohol addiction, the nicotine habituation, psychosis, the opium habituation, anxiety, vomiting, dyskinesia and depression.The brain function that other medicable indication has shunt operation or transplanting to cause is limited, cerebral blood supply insufficiency, Spinal injury, head injury, gestation cause anoxic, asystole and hypoglycemia.In addition, because of unusual in the pregnant process causes the brain function of backwardness limited, the slow or genetic abnormality of brain development, such as fragile X mental retardation, mongolism or autism pedigree obstacle (Autism spectrum disorders), also be the indication that possible can treat such as kanner's syndrome, pervasive developmental disorders (PDD), attention deficit disorder (ADD).
Formula I compound and their pharmacologically acceptable salt especially can be used as anodyne.Medicable types of pain comprise inflammatory pain such as sacroiliitis and rheumatism, vasculitis, neuropathic pain such as trigeminal neuralgia or herpetic neurodynia (herpetic neuralgia), diabetic neuropathy pain, cusalgia, hyperpathia, severe chronic pain (severe chronic pain), post-operative pain with various illnesss such as the relevant pain of cancer, stenocardia, kidney or biliary colic, menstruation, migraine and gout.
Use following method to test the pharmacological activity of described compound:
In order to carry out combination experiment, using Schlaeger and Christensen[Cytotechnology15:1-13 (1998)] will the encode cDNA transient transfection of people mGlu5a acceptor of described operation steps goes into the EBNA cell.Cytolemma homogenize thing was stored in-80 ℃ down to the same day of measuring, when the time comes they is melted, suspend again and at the 15mM of pH 7.4 Tris-HCl, 120mM NaCl, 100mMKCl, 25mM CaCl 2, 25mM MgCl 2Polytronised is to the final concentration 20 μ g protein/holes of measuring in the binding buffer liquid.
By in these films, add under 4 ℃ 12 kinds [ 3H] MPEP concentration (0.04-100nM) (cumulative volume 200 μ l) reaches 1 hour and measures saturation isotherm.With fixed concentration [ 3H] MPEP (2nM) being at war with property experiment and use 11 kinds of concentration (0.3-10,000nM) IC of evaluation test compound 50Value.Under 4 ℃, carry out hatching in 1 hour.
When hatching end, with membrane filtration the unifilter that has Filtermate 96 collectors (PackardBioScience) (have bonded in lavation buffer solution in 0.1%PEI the 96-hole of 1 hour GF/C filter membrane of preincubate white microtest plate, Packard BioScience, Meriden, CT) on, use the cold 50mM Tris-HCl damping fluid of pH7.4 to wash 3 times.Under the situation that has 10 μ MMPEP, measure non-specific binding.Add 45 μ l microscint, 40 (CanberraPackard S.A., Z ü rich, Switzerland) and jolting after 20 minutes, the radioactivity on the filter membrane is counted (3 minutes) having on the Packard Top-count microtest plate scintillometer of quench correction.
In order to carry out functional examination, as described in [B r.J.Pharmacol.128:13-20 (1999)] such as former Porter, the recombinant human mGlu5a acceptor in the HEK-293 cell is carried out [Ca 2+] i mensuration.Use Fluo4-AM (can obtain final concentration 0.2 μ M) to load dyestuff to cell by FLUKA.Use fluorescence imaging plate survey meter (FLIPR, Molecular Devices Corporation, La Jolla, CA USA) carries out [Ca 2+] i mensuration.With test compounds preincubate 5 minutes, then add the agonist that adds inferior to maximum, carry out the antagonist evaluation then.
Suppress (antagonist) curve with four parameter logarithmic equation matches, obtain IC 50, obtain the Hill coefficient with iteration non-linear curve fitting software (Xcel match).
In order to carry out the combination experiment, obtain the Ki value of test compounds.By following formula definition Ki value:
K i＝IC 50/[1+L/K d]
IC wherein 50Value for those constituting competition property radioligands ([ 3H] MPEP) the 50% test compounds concentration that suppresses.L is the concentration in conjunction with radioligand used in the experiment, the film of every batch of preparation is rule of thumb determined the K of radioligand dValue.
Compound of the present invention is the mGluR5a receptor antagonist.The activity of the formula I compound that records in the said determination method is K i＜4 μ M, preferred＜150nM.
The embodiment sequence number Ki nM The embodiment sequence number Ki nM
1 54 4 761
2 95 5 1628
3 71
The compound of formula I and pharmacologically acceptable salt thereof can be used as medicine, and for example the form with pharmaceutical preparation is used as medicine.Pharmaceutical preparation can be Orally administered, and is for example Orally administered with tablet, coating tablet, drageeing, form hard and soft gelatin capsule, solution, emulsion or suspensoid.Yet, also can rectal administration, for example with the form rectal administration of suppository, or parenteral uses, and for example uses with the form parenteral of injection solution.
Can use the pharmaceutically inert inorganic or organic carrier machining type I compound and the pharmacologically acceptable salt thereof that are used to produce pharmaceutical preparation.For example, lactose, W-Gum or derivatives thereof, talcum powder, stearic acid or its salt etc. can be used as for example this class carrier of tablet, coating tablet, drageeing and hard gelatin capsule.The suitable carriers that is used for soft gelatin capsule is for example vegetables oil, wax, fat, semisolid and liquid polyol etc.; This depends on the character of active substance.Yet, with regard to soft gelatin capsule, need not carrier usually.The suitable carriers that is used to produce solution and syrup is for example water, polyvalent alcohol, sucrose, Nulomoline, glucose etc.Assistant agent can be used for the injection of aqueous solution of the water-soluble salt of formula I compound as alcohol, polyvalent alcohol, glycerine, plant wet goods, but optional usually.The suitable carriers that is used for suppository is for example natural or winterized stearin, wax, fat, semiliquid or liquid polyol etc.
In addition, pharmaceutical preparation can contain salt, buffer reagent, sequestering agent or the antioxidant of sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, correctives, change osmotic pressure.They can also contain other treatment and go up valuable material.
As in the past mentioned, containing formula I compound or pharmaceutically acceptable salt thereof and treating the medicine of going up inert excipients also is purpose of the present invention, the method of producing this class medicine also is a purpose of the present invention, described method comprises that one or more formulas I compound or pharmaceutically acceptable salt thereof is gone up the inert carrier with one or more treatments makes the galenic formulation, if desired, wherein also add one or more other treatment and go up valuable material.
Dosage can change in grace period, and should be suitable for the individual demand in every kind of particular case certainly.Generally speaking, for all described indications, effective dose oral or that parenteral is used is 0.01-20mg/kg/ days, and preferred dose is 0.1-10mg/kg/ days.Therefore, be the grownup of 70kg for body weight, per daily dose is 0.7-1400mg/ days, preferred 7-700mg/ days.
It is in order further to illustrate the present invention that the following example is provided, but is not used for the present invention only is limited to typical compound:
Embodiment 1
3-(pyridin-3-yl amino)-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides
Step 1:3-(pyridin-3-yl amino)-pyrazine-2-methyl-formiate
Pyrazine-(0.8g, 5.2mmol) (1.2g 7.8mmol) is dissolved in the 20mL dry toluene to the 2-methyl-formiate with the 3-bromopyridine with 3-amino.Add 4, two (diphenylphosphino)-9 of 5-, and 9-dimethyl xanthene (0.6g, 1.04mmol), uncle's Sodium propanecarboxylate (0.75g, 7.8mmol) and three (dibenzalacetone) two palladium chloroform mixtures (0.54g 0.52mmol) and with this reaction mixture stirred 60 minutes under 150 ℃ and microwave irradiation.Evaporation reaction mixture and by flash chromatography on silica gel method purifying (heptane/ethyl acetate 1: 2-〉0: 100 gradient) then.Obtain required product, be brown solid (260mg, 22%), MS:m/e=231.1 (M+H +).
Step 2:3-(pyridin-3-yl amino)-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides
(140mg 1.1mmol) is dissolved in 4mL diox and be added in heptane (0.55mL, 1.1mmol) the 2M trimethyl aluminium-solution in the 3-chloroaniline.This solution at room temperature stirred 1 hour and add 3-(pyridin-3-yl amino)-pyrazine-2-methyl-formiate (127mg, 0.55mmol).This reaction mixture was stirred 2 hours down cooling and with the quencher of 0.5mL water at 80 ℃.Add sodium sulfate, stirred 10 minutes, filter and evaporation.By flash chromatography on silica gel method (heptane/ethyl acetate 1: 2-〉0: 100 gradient) purifying crude product and obtain required product, be yellow solid (13mg, 7.2%), MS:m/e=326.2 (M+H +).
Embodiment 2
3-phenyl amino-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides
Step 1:3-phenyl amino-pyrazine-2-methyl-formiate
With title compound, MS:m/e=230.3 (M+H +), separate by product as embodiment 1 step 1.
Step 2:3-phenyl amino-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides
According to the general method of embodiment 1 step 2, prepare title compound by 3-phenyl amino-pyrazine-2-methyl-formiate and 3-chloroaniline, MS:m/e=325.1 (M+H +).
Embodiment 3
3-(5-fluoro-pyridin-3-yl amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-acid amides
Step 1:3-two-(tertbutyloxycarbonyl) amino-pyrazino-2-methyl-formiate
With the amino pyrazine of 3--2-methyl-formiate (2.5g, 16.3mmol), di-tert-butyl dicarbonic acid ester (7.5g, 34.4mmol) and 4-(N, N-dimethylamino) pyridine (0.1g 0.8mmol) is dissolved in 100mL methylene dichloride and refluxing 4 hours.Cool off this reaction mixture and use saturated NaHCO 3-solution and ethyl acetate extraction.Use the dried over sodium sulfate organic extract, filter and evaporation.By flash chromatography on silica gel method purifying crude product (heptane/ethyl acetate 90: 10-〉1: 1 gradient).Obtain required compound, be white solid (4.7g, 81%), MS:m/e=354.0 (M+H +).
Step 2:[3-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-pyrazine-2-yl]-carboxylamine two uncle's fourths Ester
According to the general method of embodiment 1 step 2, by 3-two-(tertbutyloxycarbonyl) amino-pyrazino-2-methyl-formiate and 1-methyl isophthalic acid H-pyrazole-3-yl amine [1,976 52 pages of Synthesis] preparation title compound, MS:m/e=219.2 (M+H +).
Step 3:3-amino-pyrazino-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-amide hydrochloride
With [3-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-pyrazine-2-yl]-carboxylamine di tert butyl carbonate (0.65g, 1.55mmol) be dissolved in the 10mL ethyl acetate and be added in 8M HCl in the ethanol (3.9mL, 31mmol).This reaction mixture was at room temperature stirred 3 hours and used then the dilution of 20mL diisopropyl ether.Filtering solid matter and under 50 ℃ and 15mbar dry 1 hour.Obtain required compound, be yellow solid (0.37g, 94%), MS:m/e=219.3 (M+H+).
Step 4:3-(5-fluoro-pyridin-3-yl amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-acid amides
Mix 3-amino-pyrazino-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-amide hydrochloride (120mg, 0.47mmol), 3,5-difluoro pyridine (500mg, 4.4mmol), cesium carbonate (610mg, 1.89mmol) and 1mL N, dinethylformamide and under 180 ℃ and microwave irradiation, stirring 60 minutes.Use saturated NaHCO 3This reaction mixture of-solution extraction and with ethyl acetate extraction three times.With the organic extract that dried over sodium sulfate merges, filter and evaporation.By flash chromatography on silica gel method purifying crude product (heptane/ethyl acetate 90: 10-〉30: 70 gradients).Obtain required compound, be yellow solid (24mg, 16%), MS:m/e=314.0 (M+H +).
Embodiment 4
3-phenyl amino-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides
Step 1:3-bromo-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides
According to the general method of embodiment 1 step 2, by 3-bromo-pyrazine-2-methyl-formiate (embodiment A) and 2-methyl-pyridin-4-yl amine (Embodiment B) preparation title compound, MS:m/e=294.9 (M+H +).
Step 2:3-phenyl amino-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides
With 3-bromo-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides (130mg, 0.44mmol) and aniline (54mg 0.58mmol) is dissolved in the dry diox of 4mL.Add 4, two (diphenylphosphino)-9 of 5-, and 9-dimethyl xanthene (51mg, 0.09mmol), cesium carbonate (290mg, 0.89mmol) and three (dibenzalacetone) two palladium chloroform mixtures (46mg 0.044mmol) and with this reaction mixture stirred 50 minutes under 150 ℃ and microwave irradiation.Evaporate this reaction mixture then and by flash chromatography on silica gel method purifying (heptane/ethyl acetate 1: 1-〉100% ethyl acetate).Obtain required product, be yellow solid (47mg, 35%), MS:m/e=306.2 (M+H +).
Embodiment 5
3-(5-chloro-pyridin-3-yl amino)-6-methyl-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides
Step 1:3-bromo-6-methyl-pyrazine-2-ethyl formate
With 3-amino-6-methyl-pyrazine-2-ethyl formate (Embodiment C) (2.0g, 11mmol), 4mL water and 3.7mL (33.1mmol) 48% hydrobromic mixture be cooled to 5 ℃.At 5 ℃ of 2.5M NaNO that drip down in water 2-solution (5.3mL, 13.2mmol) (N 2-emit! ).This reaction mixture stirred 1 hour and impouring ice-water then.Use Na 2CO 3This reaction mixture and with twice of ethyl acetate extraction (each 200mL) neutralizes.With the organic extract that dried over sodium sulfate merges, filter and evaporation.By flash chromatography on silica gel method purifying crude product (heptane/ethyl acetate 90: 10-〉50: 50 gradients).Obtain required compound, be colourless liquid (0.53g, 20%), MS:m/e=245.1 (M+H +).
Step 2:3-bromo-6-methyl-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides
General method according to embodiment 1 step 2 prepares title compound, MS:m/e=307.2 (M+H by 3-bromo-6-methyl-pyrazine-2-ethyl formate and 2-methyl-pyridin-4-yl amine (Embodiment B) +).
Step: 3-(5-chloro-pyridin-3-yl amino)-6-methyl-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides
General method according to embodiment 4 steps 2 prepares title compound, MS:m/e=355.1 (M+H by 3-bromo-6-methyl-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides and 5-chloropyridine-3-amine +).
Embodiment 6
3-(3-fluoro-phenyl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides
Step 1:3-bromo-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides
General method according to embodiment 1 step 2 prepares title compound, MS:m/e=301.0 (M+H by 3-bromo-pyrazine-2-methyl-formiate (embodiment A) and 2-amino-4-methylthiazol +).
Step 2:3-(3-fluoro-phenyl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides
General method according to embodiment 4 steps 2 prepares title compound, MS:m/e=330.1 (M+H by 3-bromo-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides and 3-fluoroaniline +).
Embodiment 7
3-(pyridin-3-yl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides dihydrochloride
Step 1:3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-methyl-formiate
With 3-(pyridin-3-yl amino)-(embodiment 1 for pyrazine-2-methyl-formiate, step 1) (245mg, 1.06mmol), di-tert-butyl dicarbonic acid ester (255mg, 1.17mmol) and 4-(N, the N-dimethylamino) (7mg 0.05mmol) is dissolved in 100ml methylene dichloride and refluxing 2 hours to pyridine.Cool off this reaction mixture and use saturated NaHCO 3-solution and ethyl acetate extraction.Use the dried over sodium sulfate organic extract, filter and evaporation.Obtain required compound, be brown oil (364mg,＞100%), MS:m/e=331.3 (M+H +), it is used for next step without being further purified.
Step 2:3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-formic acid
(364mg 1.1mmol) is dissolved in 10ml THF with 3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-methyl-formiate.(139mg 3.30mmol) and at room temperature stirs and spends the night to add 5ml methyl alcohol, 5ml water and lithium hydroxide monohydrate.Evaporation organic solvent and with in the 2N HCl-solution and resistates.This compound is evaporated to drying and is used for next step [(405mg,＞100%), MS:m/e=315.2 (M+H-)] without being further purified.
Step 3:[3-(4-methyl-thiazol-2-yl formamyl)-pyrazine-2-yl]-pyridin-3-yl-carboxylamine uncle Butyl ester
With 3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-formic acid (405mg, 80%, 1.02mmol), 2-amino-4-methylthiazol (129mg, 1.12mmol), N, N-diisopropylethylamine (0.23ml, 1.33mmol) and TBTU (430mg 1.33mmol) is dissolved in 1ml DMF and at room temperature stir and spend the night.Water makes this reaction mixture quencher and with twice of ethyl acetate extraction.With 2N NaOH-solution, water and salt water washing organic extract, use dried over sodium sulfate, filter and evaporation.By flash chromatography on silica gel method purifying crude product (heptane/ethyl acetate 90: 10-〉40: 60 gradients).Obtain required compound, be yellow foam (195mg, 46%), MS:m/e=413.3 (M+H +).
Step 4:3-(pyridin-3-yl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides dihydrochloride
With [3-(4-methyl-thiazol-2-yl formamyl)-pyrazine-2-yl]-pyridin-3-yl-t-butyl carbamate (180mg, 0.44mmol) be dissolved in the 5ml ethyl acetate and be added in 8MHCl in the ethanol (2.2ml, 17.6mmol).This reaction mixture was at room temperature stirred 3 hours and used then the dilution of 20mL diisopropyl ether.Filtering solid matter and under 50 ℃ and 15mbar dry 1 hour.Obtain required compound, be yellow solid (169mg, 99%), MS:m/e=313.1 (M+H+).
Embodiment 8
3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides
Step 1:3-(pyrimidine-5-base is amino)-pyrazine-2-methyl-formiate
General method according to embodiment 4 steps 2 prepares title compound, MS:m/e=232.1 (M+H by the amino pyrazine of 3--2-methyl-formiate and 5-bromo pyrimi piperidine +).
Step 2:3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides
General method according to embodiment 1 step 2 prepares title compound, MS:m/e=314.0 (M+H by 3-(pyrimidine-5-base is amino)-pyrazine-2-methyl-formiate and 2-amino-4-methylthiazol +).
Embodiment 9
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (5-fluoro-pyridine-2-yl)-amide hydrochloride
Step 1:6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-ethyl formate
(800mg, 4.4mmol) (1.63g 8.0mmol) is dissolved in the dry diox of 17ml with the 3-iodine pyridine with 3-amino-6-methyl-pyrazine-2-ethyl formate (Embodiment C).Add 4, two (diphenylphosphino)-9 of 5-, and 9-dimethyl xanthene (510mg, 0.88mmol), cesium carbonate (2.30g, 7.0mmol) and three (dibenzalacetone) two palladium chloroform mixtures (460mg 0.44mmol) and with this reaction mixture stirred 16 hours down at 130 ℃.Evaporate this reaction mixture then and by flash chromatography on silica gel method purifying (heptane/ethyl acetate 9: 1-〉heptane/ethyl acetate 1: 2).Obtain required product, be yellow oil (455mg, 40%), MS:m/e=259.2 (M+H +).
Step 2:3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-ethyl formate
General method according to embodiment 8 steps 1 prepares title compound, MS:m/e=359.1 (M+H by 6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-ethyl formate +).
Step 3:3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-formic acid
General method according to embodiment 8 steps 2 prepares title compound by 3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-ethyl formate, MS:m/e=329.1 (M+H-).
Step 4:[3-(5-fluoro-pyridine-2-base formamyl)-5-methyl-pyrazine-2-yl]-pyridin-3-yl-amino T-butyl formate
General method according to embodiment 8 steps 3 prepares title compound, MS:m/e=425.2 (M+H by 3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-formic acid and 2-amino-5-fluorine pyridine +).
Step 5:6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (5-fluoro-pyridine-2-yl)-amide hydrochloride
General method according to embodiment 8 steps 4 prepares title compound, MS:m/e=325.2 (M+H by [3-(5-fluoro-pyridine-2-base formamyl)-5-methyl-pyrazine-2-yl]-pyridin-3-yl-t-butyl carbamate +).
Embodiment 10
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-amide hydrochloride
General method according to embodiment 10 prepares title compound, MS:m/e=327.1 (M+H by 3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-formic acid and 2-amino-4-methylthiazol +).
Embodiment 11
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazoles-2-yl)-amide hydrochloride
General method according to embodiment 10 prepares title compound, MS:m/e=310.3 (M+H by 3-(tertbutyloxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-formic acid and 1-methyl isophthalic acid H-pyrazoles-2-base amine [1,976 52 pages of Synthesis] +).
Embodiment 12
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (3-chloro-phenyl)-amide hydrochloride
General method according to embodiment 10 prepares title compound, MS:m/e=341.2 (M+H by 3-amino-6-methyl-pyrazine-2-ethyl formate (Embodiment C), 5-bromo pyrimi piperidine and 3-chloroaniline +).
Embodiment 13
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (5-fluoro-pyridine-2-yl)-acid amides
General method according to embodiment 10 prepares title compound, MS:m/e=326.3 (M+H by 3-amino-6-methyl-pyrazine-2-ethyl formate (Embodiment C), 5-bromo pyrimi piperidine and 2-amino-5-fluorine pyridine +).
Embodiment 14
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazoles-2-yl)-amide hydrochloride
General method according to embodiment 10 prepares title compound, MS:m/e=311.2 (M+H by 3-amino-6-methyl-pyrazine-2-ethyl formate (Embodiment C), 5-bromo pyrimi piperidine and 1-methyl isophthalic acid H-pyrazoles-2-base amine [1,976 52 pages of Synthesis] +).
Embodiment 15
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (2-methyl-thiazole-4-yl)-amide hydrochloride
General method according to embodiment 10 prepares title compound, MS:m/e=328.1 (M+H by 3-amino-6-methyl-pyrazine-2-ethyl formate (Embodiment C), 5-bromo pyrimi piperidine and 4-amino-2-methyl thiazole (embodiment D) +).
Embodiment 16
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides
General method according to embodiment 10 prepares title compound by 3-amino-6-methyl-pyrazine-2-ethyl formate (Embodiment C), 5-bromo pyrimi piperidine and 2-amino-4-methylthiazol, MS:m/e=328.3 (M+H+).
Synthesizing of intermediate
Embodiment A
3-bromo-pyrazine-2-methyl-formiate
Described in document, prepare title compound, MS:m/e=218.9 (M+H+) by the amino pyrazine of 3--2-methyl-formiate by the Sandmeyer reaction.
Embodiment B
2-methyl-pyridin-4-yl amine
Described in document, prepare title compound by hydrogenation 4-nitro-2-PICOLINE N-OXIDES.
Embodiment C
3-amino-6-methyl-pyrazine-2-ethyl formate
Step 1:3-amino-6-methyl-4-oxygen base-pyrazine-2-ethyl formate (3-amono-6-methyl-4-oxy- Pyrazine-2-carboxylic acid ethyl ester)
(11.2g, 87.3mmol) [J.Med.Chem 1997,40,2196-2210] are dissolved in 50ml acetate and at room temperature drip pyruvic aldehyde-1-oxime (10.4g, 119.4mmol) solution (heat release in 50ml acetate with amino-cyano group-ethyl acetate!-ice-bath cooling).Dark brown mixture at room temperature stirred spend the night and use the quencher of 100ml water then.Evaporate this reaction mixture and water extracting twice (each 100ml) and with ethyl acetate extraction three times (each 200ml).With the organic extract that dried over sodium sulfate merges, filter and evaporation.By flash chromatography on silica gel method purifying crude product (heptane/ethyl acetate 90: 10-〉0: 100 gradient).Obtain required compound, be yellow solid (7.1g, 30%), MS:m/e=198.2 (M+H +).
Step 2:3-amino-6-methyl-pyrazine-2-ethyl formate
(7.1g 36mmol) is dissolved in 350ml ethanol and at room temperature used Raney nickel hydrogenation 3 hours with 3-amino-6-methyl-4-oxygen base-pyrazine-2-ethyl formate.Filter this reaction mixture and evaporation.Obtain required crude product, be used for next step (6.6g, 100%), MS:m/e=182.1 (M+H for the light brown solid and without any being further purified +).
Embodiment D
4-amino-2-methyl thiazole
Prepare title compound according to the preparation method described in EP 321115 patents.
The preparation of drug combination that comprises The compounds of this invention:
Example I
Produce the tablet of following composition in a conventional manner:
The mg/ sheet
Active ingredient 100
Lactose powder 95
White cornstarch 35
Polyvinylpyrrolidone 8
Carboxymethyl starch Na 10
Magnesium Stearate 2
Sheet is heavy 250
Example II
Produce the tablet of following composition in a conventional manner:
The mg/ sheet
Active ingredient 200
Lactose powder 100
White cornstarch 64
Polyvinylpyrrolidone 12
Carboxymethyl starch Na 20
Magnesium Stearate 4
Sheet is heavy 400
EXAMPLE III
Produce the capsule of following composition:
The mg/ capsule
Active ingredient 50
Crystallization lactose 60
Microcrystalline Cellulose 34
Talcum powder 5
Magnesium Stearate 1
The capsule filling weight 150
Active ingredient, crystallization lactose and the Microcrystalline Cellulose that will have suitable granular size uniform mixing, screening and after this mix talcum powder and Magnesium Stearate each other.Final mixture is packed in the hard gelatin capsule of suitable size.

Claims (37)

1. the compound of general formula (I):
Figure S200680007159XC00011
Wherein
R 1For having formula (II) or 5-(III) or 6-unit ring separately:
Figure S200680007159XC00012
R 2Be H, C 1-C 7-alkyl, C 3-C 6-cycloalkyl or-(CH 2) m-R a
R 3Be H, the aryl or the heteroaryl that are randomly replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,
-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R d
Perhaps randomly by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R 5Be C 1-C 7-alkyl, C 1-C 7-alkyl-C 3-C 6-cycloalkyl;-(CH 2) n-O-R f, C 3-C 8-alkenyl-O-R f,-(CH 2) n-NR gR h-C 2-C 6-alkenyl-NR gR hOr-(CH 2) n-R e
R aFor-O-C 1-C 7-alkyl or-OH;
R bBe C 1-C 7-alkyl, NH 2Or-O-C 1-C 7-alkyl;
R cFor-OH, NH 2Or NH-(CO)-O-C 1-C 7-alkyl;
R dBe C 1-C 7-alkyl ,-NH 2,-NH-C 1-C 7-alkyl or-N-two (C 1-C 7-alkyl);
R eFor-OH ,-CH 2F ,-CHF 2,-CF 3Or-O-(CO)-C 1-C 7-alkyl;
R fBe C 1-C 7-alkyl, C 3-C 8-alkenyl, C 3-C 6-cycloalkyl, phenyl, benzyl or-(CO)-R ';
R g, R hBe H, C independently 1-C 7-alkyl, C 3-C 6-cycloalkyl, C 3-C 8-alkenyl, phenyl, benzyl or-(CO)-R ', perhaps R gAnd R hAlso can form 5-to the 7-unit's heterocycle or the heteroaryl ring that are randomly replaced with the nitrogen-atoms that they connected by 1 or 2 OH;
R ' is NH 2,-NH-C 1-C 7-alkyl, C 1-C 7-alkyl or C 1-C 7-alkoxyl group;
M is 1 to 4;
N is 2 to 6;
And pharmacologically acceptable salt.
2. the compound of the formula of claim 1 (I):
Figure S200680007159XC00021
Wherein
R 1For having formula (II) or 5-(III) or 6-unit ring separately:
Figure S200680007159XC00031
R 2Be H, C 1-C 7-alkyl, C 3-C 6-cycloalkyl or-(CH 2) m-R a
R 3Be optional aryl or the heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R 5Be C 1-C 7-alkyl or C 1-C 7-alkyl-C 3-C 6-cycloalkyl;-(CH 2) n-O-R f, C 3-C 8-alkenyl-O-R f,-(CH 2) n-NR gR h-C 2-C 6-alkenyl-NR gR hOr-(CH 2) n-R e
R aFor-O-C 1-C 7-alkyl or-OH;
R bBe C 1-C 7-alkyl, NH 2, or-O-C 1-C 7-alkyl;
R cFor-OH, NH 2Or NH-(CO)-O-C 1-C 7-alkyl;
R dBe C 1-C 7-alkyl ,-NH 2,-NH-C 1-C 7-alkyl or-N-two (C 1-C 7-alkyl);
R eFor-OH ,-CH 2F ,-CHF 2,-CF 3Or-O-(CO)-C 1-C 7-alkyl;
R fBe C 1-C 7-alkyl, C 3-C 8-alkenyl, C 3-C 6-cycloalkyl, phenyl, benzyl or-(CO)-R ';
R g, R hBe H, C independently 1-C 7-alkyl, C 3-C 6-cycloalkyl, C 3-C 8-alkenyl, phenyl, benzyl or-(CO)-R ' or R gAnd R hCan also form optional 5-to 7-unit's heterocycle or the heteroaryl ring that is replaced by 1 or 2 OH with the nitrogen-atoms that they connected;
R ' is NH 2,-NH-C 1-C 7-alkyl, C 1-C 7-alkyl or C 1-C 7-alkoxyl group;
M is 1 to 4;
N is 2 to 6;
And pharmacologically acceptable salt.
3. the compound of the formula of claim 1 (Ia)
Figure S200680007159XC00041
R wherein 2, R 3And R 4As definition in the claim 1.
4. the compound of the formula of claim 3 (Ia), wherein
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
5. the compound of the formula of claim 4 (Ia), wherein it is 6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-amide hydrochloride.
6. the compound of the formula of claim 1 (Ib)
Figure S200680007159XC00051
R wherein 2, R 3And R 4As defined in claim 1.
7. the compound of the formula of claim 6 (Ib), wherein
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
8. the compound of the formula of claim 7 (Ib), wherein it is 6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (2-methyl-thiazole-4-yl)-amide hydrochloride.
9. the compound of the formula of claim 1 (Ic)
Figure S200680007159XC00052
R wherein 2, R 3And R 4As definition in the claim 1.
10. the compound of the formula of claim 9 (Ic), wherein
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
11. the compound of the formula of claim 10 (Ic), wherein they are selected from:
3-(3-fluoro-phenyl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides;
3-(pyridin-3-yl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides dihydrochloride;
3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides;
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-amide hydrochloride; With
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (4-methyl-thiazol-2-yl)-acid amides.
12. the compound of the formula of claim 1 (Id)
Figure S200680007159XC00061
R wherein 2, R 3And R 5As definition in the claim 1.
13. the compound of the formula of claim 12 (Id), wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 5Be C 1-C 7-alkyl or C 1-C 7-alkyl-C 3-C 6-cycloalkyl;-(CH 2) n-O-R f, C 3-C 8-alkenyl-O-R f,-(CH 2) n-NR gR h-C 2-C 6-alkenyl-NR gR hOr-(CH 2) n-R e
R b, R c, R d, R e, R f, R g, R h, m and n be as definition in the claim 1,
And pharmacologically acceptable salt.
14. the compound of the formula of claim 13 (Id), wherein they are selected from:
3-(5-fluoro-pyridin-3-yl amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-acid amides;
6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-amide hydrochloride; With
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (1-methyl isophthalic acid H-pyrazole-3-yl)-amide hydrochloride.
15. the compound of the formula of claim 1 (Ie)
Figure S200680007159XC00071
R wherein 2, R 3And R 4As definition in the claim 1.
16. the compound of the formula of claim 15 (Ie), wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
17. the compound of the formula of claim 1 (If)
Figure S200680007159XC00081
R wherein 2, R 3And R 4As definition in the claim 1.
18. the compound of the formula of claim 17 (If), wherein
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
19. the compound of the formula of claim 1 (Ig)
Figure S200680007159XC00082
R wherein 2, R 3And R 4As definition in the claim 1.
20. the compound of the formula of claim 19 (Ig), wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
21. the compound of the formula of claim 1 (Ih)
R wherein 2, R 3And R 4As definition in the claim 1.
22. the compound of the formula of claim 21 (Ih), wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
23. the compound of the formula of claim 1 (Ii)
Figure S200680007159XC00092
R wherein 2, R 3And R 4As definition in the claim 1.
24. the compound of the formula of claim 23 (Ii), wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
25. the compound of the formula of claim 24 (Ii), wherein it is 6-methyl-3-(pyridin-3-yl amino)-pyrazine-2-formic acid (5-fluoro-pyridine-2-yl)-amide hydrochloride; Or
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (5-fluoro-pyridine-2-yl)-acid amides.
26. the compound of the formula of claim 1 (Ij)
Figure S200680007159XC00101
R wherein 2, R 3And R 4As definition in the claim 1.
27. the compound of the formula of claim 26 (Ij), wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
28. the compound of the formula of claim 27 (Ij), wherein they are selected from:
3-(pyridin-3-yl amino)-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides;
3-phenyl amino-pyrazine-2-formic acid (3-chloro-phenyl)-acid amides; With
6-methyl-3-(pyrimidine-5-base is amino)-pyrazine-2-formic acid (3-chloro-phenyl)-amide hydrochloride.
29. the compound of the formula of claim 1 (Ik)
Figure S200680007159XC00111
R wherein 2, R 3And R 4As definition in the claim 1.
30. the compound of the formula of claim 29 (Ik), wherein:
R 2Be H or C 1-C 7-alkyl;
R 3Be H, optional phenyl or 5-or the 6-unit heteroaryl that is replaced by following groups:
CN, Cl, F, Br, CF 3, CHF 2Or-O-C 1-C 7-alkyl ,-(CO)-R b,-(CH 2) m-R c,-NH-(CO)-C 1-C 7-alkyl;-O-CH 2F ,-O-CHF 2,-O-CF 3,-S (O) 2-R dOr it is optional by C 1-C 7The heteroaryl that-alkyl replaces;
R 4For H ,-OH, Cl, F, Br, CN ,-CHF 2, CF 3, C 1-C 7-alkyl ,-O-(CO)-C 1-C 7-alkyl or-(CH 2) m-R e
R b, R c, R d, R eWith m as in the claim 1 definition,
And pharmacologically acceptable salt.
31. the compound of the formula of claim 30 (Ik), wherein they are selected from:
3-phenyl amino-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides; With
3-(5-chloro-pyridin-3-yl amino)-6-methyl-pyrazine-2-formic acid (2-methyl-pyridin-4-yl)-acid amides.
32. comprise the medicine as any described one or more compounds and pharmaceutically acceptable vehicle in the claim 1 to 31, it is used for the treatment of and prevents the receptor-mediated obstacle of mGluR5.
33. the medicine of claim 32, it is used for the treatment of and prophylaxis of acute and/or chronic neurological disorder, anxiety, treat chronic and acute pain, the urinary incontinence, obesity, behavior disorder, obsession (OCD), gastroesophageal reflux disease (GERD), fragile X mental retardation, eating disorder, preferred anorexia and Bulimia nerovsa.
34. be used for the treatment of or prevent in the claim 1 to 31 of the receptor-mediated obstacle of mGluR5 any described compound with and pharmacologically acceptable salt.
35. in the claim 1 to 31 any described compound with and pharmacologically acceptable salt in the purposes of preparation in the medicine, described medicine is used for the treatment of and prevents the receptor-mediated obstacle of mGluR5.
36. the purposes in the preparation medicine of claim 35, described medicine is used for the treatment of and prophylaxis of acute and/or chronic neurological disorder, anxiety, treat chronic and acute pain, the urinary incontinence, obesity, behavior disorder, obsession (OCD), gastroesophageal reflux disease (GERD), fragile X mental retardation, eating disorder, preferred anorexia and Bulimia nerovsa.
37. the present invention as indicated above.
CN200680007159XA 2005-03-04 2006-03-02 Pyrazine -2-carboxamide derivatives as mglur5 antagonists Expired - Fee Related CN101208311B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05101704 2005-03-04
EP05101704.4 2005-03-04
PCT/EP2006/001879 WO2006094691A1 (en) 2005-03-04 2006-03-02 PYRAZINE -2-CARBOXAMIDE DERIVATIVES AS mGluR5 ANTAGONISTS

Publications (2)

Publication Number Publication Date
CN101208311A true CN101208311A (en) 2008-06-25
CN101208311B CN101208311B (en) 2013-06-12

Family

ID=36518434

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200680007159XA Expired - Fee Related CN101208311B (en) 2005-03-04 2006-03-02 Pyrazine -2-carboxamide derivatives as mglur5 antagonists

Country Status (16)

Country Link
US (2) US20060199828A1 (en)
EP (1) EP1858862B1 (en)
JP (1) JP4774410B2 (en)
KR (1) KR100929941B1 (en)
CN (1) CN101208311B (en)
AR (1) AR053153A1 (en)
AU (1) AU2006222252B2 (en)
BR (1) BRPI0609256A2 (en)
CA (1) CA2600169C (en)
IL (1) IL185327A0 (en)
MX (1) MX2007010563A (en)
NO (1) NO20074287L (en)
RU (1) RU2407739C2 (en)
TW (1) TWI310378B (en)
WO (1) WO2006094691A1 (en)
ZA (1) ZA200707139B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106317027A (en) * 2015-06-15 2017-01-11 山东轩竹医药科技有限公司 Heteroaryl amide derivative and use thereof as TGR5 agonist
CN107011272A (en) * 2011-10-28 2017-08-04 霍夫曼-拉罗奇有限公司 Pyrazines derivatives
CN115244036A (en) * 2020-02-27 2022-10-25 先正达农作物保护股份公司 Pesticidally active diazine-bisamide compounds

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076555A1 (en) * 1999-06-11 2000-12-21 Pro Duct Health, Inc. Gel composition for filing a breast milk duct prior to surgical excision of the duct or other breast tissue
JPWO2008156174A1 (en) * 2007-06-21 2010-08-26 大正製薬株式会社 Pyrazineamide compound
GB0713686D0 (en) * 2007-07-13 2007-08-22 Addex Pharmaceuticals Sa New compounds 2
CN101939054B (en) 2007-12-10 2014-10-29 诺华股份有限公司 organic compounds
WO2009078432A1 (en) * 2007-12-18 2009-06-25 Taisho Pharmaceutical Co., Ltd. 1-alkyl-4-amino-1h-pyrazole-3-carboxamide compound
US8569308B2 (en) * 2009-09-17 2013-10-29 Vanderbilt University Substituted heteroarylamine carboxamide analogs as mGluR5 negative allosteric modulators and methods of making and using the same
US8470820B2 (en) 2010-01-22 2013-06-25 Hoffman-La Roche Inc. Nitrogen-containing heteroaryl derivatives
US8703768B2 (en) 2010-06-09 2014-04-22 Hoffmann-La Roche Inc. Nitrogen containing heteroaryl compounds
JP2014515008A (en) 2011-03-03 2014-06-26 ヴァンダービルト ユニバーシティー 6-Alkyl-N- (pyridin-2-yl) -4-aryloxypicolinamide analogs as negative allosteric modulators of MGLUR5 and methods of making and using the same
EP3071568A1 (en) 2013-11-19 2016-09-28 Vanderbilt University Substituted imidazopyridine and triazolopyridine compounds as negative allosteric modulators of mglur5
UA117779C2 (en) * 2014-02-14 2018-09-25 Такеда Фармасьютікал Компані Лімітед Pyrazines modulators of gpr6
US9533982B2 (en) 2014-03-20 2017-01-03 Vanderbilt University Substituted bicyclic heteroaryl carboxamide analogs as mGluR5 negative allosteric modulators
US9550778B2 (en) 2014-10-03 2017-01-24 Vanderbilt University Substituted 6-aryl-imidazopyridine and 6-aryl-triazolopyridine carboxamide analogs as negative allosteric modulators of mGluR5
JP6779204B2 (en) * 2014-11-18 2020-11-04 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Aminopyrazine compound with A2A antagonist properties
WO2016144792A1 (en) * 2015-03-06 2016-09-15 Alpharmagen, Llc Alpha 7 nicotinic acetylcholine receptor allosteric modulators, their derivatives and uses thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0321115B1 (en) 1987-12-14 1991-08-14 Sawai Pharmaceutical Co., Ltd. Carboxamide derivatives having tetrazole and thiazole rings and their use
US20070149547A1 (en) 2004-02-12 2007-06-28 Celine Bonnefous Bipyridyl amides as modulators of metabotropic glutamate receptor-5
BRPI0607583A2 (en) 2005-03-04 2009-09-15 Hoffmann La Roche pyridin-2-carboxamide derivatives as mglur5 antagonists, method for their preparation, medicament containing same as well as use related to said compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107011272A (en) * 2011-10-28 2017-08-04 霍夫曼-拉罗奇有限公司 Pyrazines derivatives
CN106317027A (en) * 2015-06-15 2017-01-11 山东轩竹医药科技有限公司 Heteroaryl amide derivative and use thereof as TGR5 agonist
CN115244036A (en) * 2020-02-27 2022-10-25 先正达农作物保护股份公司 Pesticidally active diazine-bisamide compounds

Also Published As

Publication number Publication date
CN101208311B (en) 2013-06-12
NO20074287L (en) 2007-12-03
ZA200707139B (en) 2008-10-29
RU2007132656A (en) 2009-04-10
IL185327A0 (en) 2008-02-09
TWI310378B (en) 2009-06-01
EP1858862B1 (en) 2016-04-20
AR053153A1 (en) 2007-04-25
US7947685B2 (en) 2011-05-24
WO2006094691A1 (en) 2006-09-14
JP2008531630A (en) 2008-08-14
TW200700396A (en) 2007-01-01
RU2407739C2 (en) 2010-12-27
CA2600169C (en) 2013-11-05
US20090233944A1 (en) 2009-09-17
MX2007010563A (en) 2007-10-04
CA2600169A1 (en) 2006-09-14
AU2006222252B2 (en) 2012-02-16
KR20070107101A (en) 2007-11-06
EP1858862A1 (en) 2007-11-28
US20060199828A1 (en) 2006-09-07
JP4774410B2 (en) 2011-09-14
BRPI0609256A2 (en) 2010-03-09
AU2006222252A1 (en) 2006-09-14
KR100929941B1 (en) 2009-12-04

Similar Documents

Publication Publication Date Title
CN101208311A (en) Pyrazine-2-carboxamide derivatives as mGluR5 antagonists
CN101133027B (en) Pyridine-2-carboxamide derivatives as MGLUR5 antagonists
AU2017201873B2 (en) PDE9i with imidazo pyrazinone backbone
CN113544128A (en) KRAS-G12C inhibitors
EP3013813B1 (en) Heteroaromatic compounds and their use as dopamine d1 ligands
DE69826883T2 (en) HETEROARYL DIAZACYCLOALKANE AS CHOLINERGIC LIGAND FOR NICOTIN ACETYLCHOLINE RECEPTORS
EP2456440B1 (en) Quinolinone pde2 inhibitors
CN101384554A (en) Pyridine-2-carboxamide derivatives
CN100358889C (en) Imidazol-4-yl-ethynyl-pyridine derivatives
CN110114351B (en) Heterocyclic inhibitors of MCT4
DE60315062T2 (en) TRIAZONE COMPOUNDS FOR THE TREATMENT OF DYSMENORRHOE
CN102482227A (en) Substituted Triazole And Imidazole Derivatives As Gamma Secretase Modulators
WO2007038669A9 (en) Diarylamine-containing compounds and compositions, and their use as modulators of c-kit receptors
CN105814022A (en) Fused bicyclic heteroaromatic derivatives as modulators of tnf activity
TW200536829A (en) Tetrahydroquinoline derivatives and a process for preparing the same
JP2009527562A (en) Cinnoline derivatives as phosphodiesterase 10 inhibitors
CA2644850A1 (en) Quinoline and isoquinoline derivatives as phosphodiesterase 10 inhibitors
CN109535161A (en) Triazolo pyrimidine analog derivative, preparation method and its application in medicine
CN101679272B (en) Triazolo [1, 5-a] quinolines as adenosine A3 receptor ligands
TW201431857A (en) Heteroaromatic compounds and their use as dopamine D1 ligands
CN101291939A (en) Thiazolo[4,5-C]pyridine derivatives as mGluR5 receptor antagonists
CN101166529B (en) Benzotriazole derivatives as cannabinoid receptor antagonists
CA2205584A1 (en) (thiophen-2-yl)-piperidin or tetrahydropyridin carboxamides
CN101277958B (en) Naphthyridin derivatives
KR102333854B1 (en) Novel pyridinyltriazine derivatives as protein kinase inhibitors and compositions for preventing, improving or treating cancer containing the same

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20130612

Termination date: 20170302

CF01 Termination of patent right due to non-payment of annual fee